Therapeutic thiazolidinone compounds

ABSTRACT

Thiazolidinone compounds, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis.

FIELD OF THE INVENTION

This invention relates to chemical compounds that inhibit cholesterolester transfer protein (CETP) and are expected to have utility inraising HDL-C, lowering LDL-C, and in the treatment and prevention ofatherosclerosis.

BACKGROUND OF THE INVENTION

Atherosclerosis and its clinical consequences, including coronary heartdisease (CHD), stroke and peripheral vascular disease, represent a trulyenormous burden to the health care systems of the industrialized world.In the United States alone, approximately 13 million patients have beendiagnosed with CHD, and greater than one half million deaths areattributed to CHD each year. Further, this toll is expected to grow overthe next quarter century as an epidemic in obesity and diabetescontinues to grow.

It has long been recognized that in mammals, variations in circulatinglipoprotein profiles correlate with the risk of atherosclerosis and CHD.The clinical success of HMG-CoA reductase inhibitors, especially thestatins, in reducing coronary events is based on the reduction ofcirculating low density lipoprotein cholesterol (LDL-C), levels of whichcorrelate directly with an increased risk for atherosclerosis. Morerecently, epidemiologic studies have demonstrated an inverserelationship between high density lipoprotein cholesterol (HDL-C) levelsand atherosclerosis, leading to the conclusion that low serum HDL-Clevels are associated with an increased risk for CHD.

Metabolic control of lipoprotein levels is a complex and dynamic processinvolving many factors. One important metabolic control in man is thecholesteryl ester transfer protein (CETP), a plasma glycoprotein thatcatalyzes the movement of cholesteryl esters from HDL to the apoBcontaining lipoproteins, especially VLDL (see Hesler, C. B., et. al.(1987) Purification and characterization of human plasma cholesterylester transfer protein. J. Biol. Chem. 262(5), 2275-2282)). Underphysiological conditions, the net reaction is a heteroexchange in whichCETP carries triglyceride to HDL from the apoB lipoprotein andtransports cholesterol ester from HDL to the apoB lipoprotein.

In humans, CETP plays a role in reverse cholesterol transport, theprocess whereby cholesterol is returned to the liver from peripheraltissues. Intriguingly, many animals do not possess CETP, includinganimals that have high HDL levels and are known to be resistant tocoronary heart disease, such as rodents (see Guyard-Dangremont, V., et.al., (1998) Phospholipid and cholesteryl ester transfer activities inplasma from 14 vertebrate species. Relation to atherogenesissusceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3),517-525). Numerous epidemiologic studies correlating the effects ofnatural variation in CETP activity with respect to coronary heartdisease risk have been performed, including studies on a small number ofknown human null mutations (see Hirano, K.-I., Yamashita, S. andMatsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl estertransfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studieshave clearly demonstrated an inverse correlation between plasma HDL-Cconcentration and CETP activity (see Inazu, A., et. al. (2000)Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin.Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologicinhibition of CETP lipid transfer activity may be beneficial to humansby increasing levels of HDL-C while lowering LDL-C.

Despite the significant therapeutic advance that statins such assimvastatin and atorvastatin represent, statins only achieve a riskreduction of approximately one-third in the treatment and prevention ofatherosclerosis and ensuing atherosclerotic disease events. Currently,few pharmacologic therapies are available that favorably raisecirculating levels of HDL-C. Certain statins and some fibrates offermodest HDL-C gains. Niacin provides an effective therapy for raisingHDL-C but suffers from patient compliance issues, due in part to sideeffects such as flushing. Drugs that inhibit CETP (CETP inhibitors) havebeen under development with the expectation that they will effectivelyraise HDL cholesterol levels and also reduce the incidence ofatherosclerosis in patients. Torcetrapib was the first drug that wastested in a long-term outcomes clinical trial. The clinical trial oftorcetrapib was terminated early due to a higher incidence of mortalityin patients to whom torcetrapib and atorvastatin were administeredconcomitantly compared with patients who were treated with atorvastatinalone. The cause of the increased mortality is not completelyunderstood, but it is not believed to be associated with the CETPinhibiting effects of the drug. Dalcetrapib was recently tested in aPhase III outcomes trial, which was terminated early because the interimdata did not show a clinical benefit. There were no safety issuesdetected for dalcetrapib.

Anacetrapib is currently the only CETP inhibitor being tested in a largescale Phase III clinical outcomes trial. Data from the recentlycompleted DEFINE Phase II/III trial of anacetrapib are promising.Patients who were treated with anacetrapib along with baseline statintherapy showed an increase of HDL-C of 138% and a decrease of LDL-C of40% compared with patients who were treated with just a statin. See: N.Engl. J. Med. 2010: 363: 2406-15. The DEFINE study was not carried outon a large enough scale to serve as a pivotal outcomes trial, but thedata in the DEFINE trial were sufficient to indicate that an increase inmortality for patients treated with anacetrapib is unlikely. Additionaldrug candidates are in development. Evacetrapib currently appears to bethe next CETP inhibitor that will proceed to a Phase III outcomes trial.Additional compounds are being sought that may have properties that areadvantageous compared with the CETP inhibitors that have so far beenstudied or are currently being studied. Such properties may include, forexample, higher potency, reduced off-target activity, betterpharmacodynamics, higher bioavailability, or a reduced food effectcompared with many of the highly lipophilic compounds that have so farbeen studied. “Food effect” refers to the variability in exposure to theactive drug that occurs depending on when the patient had last eaten,whether or not the drug is administered with food, and the fat contentof the food.

SUMMARY OF THE INVENTION

The compound of Formula I, or a pharmaceutically acceptable saltthereof, is a potent CETP inhibitor, having the utilities describedbelow. In the compound of Formula I,

Each R is independently H or —C₁-C₃alkyl;

R¹ is H or —C₁-C₃ alkyl, wherein —C₁-C₃ alkyl is optionally substitutedwith 1-5 halogens;

A and B are each A¹ or A², wherein one of A and B is A¹ and the other ofA and B is A²,

A¹ has the structure:

-   -   wherein D is selected from the group consisting of:    -   (a) phenyl, and    -   (b) HET(1);

wherein ring D comprises at least two carbon atoms that are bonded toeach other, wherein one of the two carbon atoms that are bonded to eachother in ring D is connected to the group A³ and the other of the twocarbon atoms that are bonded to each other in ring D is connected to theremainder of the structure of Formula I, so that A³ and the remainder ofthe structure of formula I are ortho to each other on ring D;

wherein HET(1) is a monocyclic 5-8-membered heterocyclic orheteroaromatic ring having 1-4 heteroatom groups independently selectedfrom N, NH, S, O, —S(O)—, —S(O)₂—, —C(═O)—, and —N(O)—, wherein HET(1)optionally comprises 1-4 double bonds;

A³ is

-   -   (a) phenyl, or    -   (b) HET(1), wherein

A³ is optionally substituted with 1-5 substituent groups independentlyselected from R^(a) and optionally one or two groups X;

provided that when B is A¹, and D and A³ are both phenyl, then A² isHET(1), or A³ is substituted with one group X, wherein X is phenyl orHET(1);

A² is

-   -   (a) phenyl,    -   (b) HET(1), or    -   (c) —C₃-C₈ cycloalkyl optionally having 1-3 double bonds;

wherein A² is optionally substituted with 1-5 substituent groupsindependently selected from R^(a);

Each R^(a) is independently selected from the group consisting of —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —OC₂-C₆alkenyl,—OC₂-C₆alkynyl, —C(═O)C₁-C₆alkyl, —C(═O)H, —OH, —NR⁶R⁷, —C(═O)NR⁶R⁷,—NR⁶C(═O)OC₁-C₆ alkyl, —NR⁶C(═O)NR⁶R⁷, —S(O)_(x)C₁-C₆ alkyl,—S(O)_(y)NR⁶R⁷, —NR⁶S(O)_(y)NR⁶R⁷, —NR⁶S(O)_(y)C₁-C₆ alkyl, halogen,—CN, —NO₂, or a 3-7-membered heterocycle having 1-3 heteroatoms whichare independently N, S or O, and optionally one group —C(═O)—, whereinthe heterocycle optionally has 1-3 double bonds and is optionallysubstituted with 1-3 substituent groups which are independently halogen,CH₃, CF₃, —OCH₃, or —OCF₃;

wherein for compounds in which. R^(a) is selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C(═O)C₁-C₆alkyl,—NR⁶C(═O)OC₁-C₆ alkyl, —S(O)_(x)C₁-C₆ alkyl, and —NR⁶S(O)_(y)C₁-C₆alkyl, R^(a) is optionally substituted with 1-11 halogens;

X is (a) C₃-C₈cycloalkyl which optionally comprises 1-2 double bonds andwhich is optionally substituted with 1-2 groups D1 and optionally with1-5 substituent groups which are independently halogen, C₁-C₅ alkyl,—OC₁-C₅ alkyl, —CN, or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl areoptionally substituted with 1-11 halogens and optionally 1-2 groups —OH;(b) C₁-C₅ alkyl which is optionally substituted with 1-2 groups D1 andoptionally with 1-2 —OH and 1-11 halogens; (c) phenyl which isoptionally substituted with 1-2 groups D1 and optionally with 1-5substituent groups which are halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, —CN,or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionally substitutedwith 1-11 halogens and optionally 1-2 groups —OH; (d) HET(1) which isoptionally substituted with 1-2 groups D1 and optionally with 1-5substituent groups which are halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, —CN,or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionally substitutedwith 1-11 halogens and optionally with 1-2 groups —OH; or (e) D1;

D¹ is —CO₂R⁸, —C(O)NR⁶R⁷, SO₂NR⁶R⁷, or HET(1);

R⁶ and R⁷ are each independently H or —C₁₋₅alkyl;

R⁸ is H or —C₁₋₅alkyl optionally substituted with 1-7 halogens;

p is an integer from 0-4;

x is 0, 1, or 2; and

y is 1 or 2.

In the compound of Formula I or Formula II, and in subgroups and otherembodiments of the invention, alkyl groups and substituents based onalkyl groups, such as alkoxy, may be linear or branched unless otherwiseindicated.

In general, references to the compound(s) of formula I or II are meantto also include subsets of compounds of formula I and II as may bedefined herein, and also are meant to include the specific numberedexamples provided herein.

DETAILED DESCRIPTION OF THE INVENTION

In further embodiments of the invention, the substituent groups definedabove may have alternative values independent of one another, as writtenbelow. Such embodiments include pharmaceutically acceptable salts whensuch salts are possible.

In some embodiments, B is A¹ and A is A².

In some embodiments, B is A² and A is A¹.

In some embodiments, each R is H or CH₃.

In some embodiments, p is an integer from 0-2.

In some embodiments, p is 0 or 1.

In some embodiments, p is 0.

In some embodiments, R is H.

In some embodiments, D and A³ are each independently phenyl, pyridyl,isoxazolyl, thienyl, imidazolyl, furyl, pyrrolyl, pyrazolyl,N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl, 1,2,4-triazolyl,tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, tetrahydropyranyl, or tetrahydrofuryl.

In some embodiments, A² is phenyl, thienyl, imidazolyl, furyl,1,3-thiazolyl, 1,3-oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl,tetrazolyl, pyridyl, N-oxido-pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, ortetrahydrofuryl.

In some embodiments, R¹ is CH₃.

In some embodiments, B is A¹, wherein A¹ has the structure of formulaII:

wherein Y¹, Y², and Y³ are each N or —CH—, wherein —CH— is optionallysubstituted with R^(a2) in place of H.

In some embodiments, R^(a1) is (a) a 3-7-membered heterocycle having 1-2heteroatoms which are independently N, S or O, and optionally one group—C(═O)— wherein the heterocycle optionally has 1-3 double bonds and isoptionally substituted with 1-3 substituent groups which areindependently halogen, CH₃, CF₃, —OCH₃, or —OCF₃; (b) —NR⁶R⁷; (c)—N(C₁-C₃ alkyl)(SO₂C₁-C₃alkyl); (d) C₁-C₃ alkyl optionally substitutedwith 1-7 halogens; (e) —OC₁-C₃ alkyl optionally substituted with 1-7halogens; and (f) —SC₁-C₃ alkyl optionally substituted with 1-7halogens.

In some embodiments, each R^(a2) is optionally halogen, CH₃, CF₃, —OCH₃,or —OCF₃.

In some embodiments, A is A², wherein A² is phenyl or pyridyl optionallysubstituted with 1-3 groups which are independently halogen, CH₃, CF₃,—OCH₃, —OCF₃, or —CN.

In some embodiments, A³ is phenyl or pyridyl, which is optionallysubstituted with one group X and with 1-4 substituent groups which areindependently halogen, C₁-C₃ alkyl optionally substituted with 1-7halogens, or —OC₁-C₃ alkyl optionally substituted with 1-7 halogens.

In some embodiments, X is (a) C₃-C₇cycloalkyl optionally substitutedwith one group D1, and cycloalkyl is optionally substituted with 1-3substituent groups which are independently halogen, —OH, C₁-C₃ alkyl, or—OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionallysubstituted with 1-5 halogens and optionally with 1-2 groups —OH; (b)C₁-C₃ alkyl-D1 in which alkyl is optionally substituted with 1-7halogens and optionally with 1-2 —OH; (c) phenyl optionally substitutedwith one group D1, wherein phenyl is optionally substituted with 1-3substituent groups which are halogen, —OH, C₁-C₃ alkyl, or —OC₁-C₃ alkylin which C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionally substituted with1-7 halogens and optionally with 1-2 OH; (d) pyridyl which is optionallysubstituted with one group D1, wherein pyridyl is optionally substitutedwith 1-3 substituent groups which are halogen, —OH, C₁-C₃ alkyl, or—OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and —OC₁-C₃ alkyl are optionallysubstituted with 1-7 halogens and optionally with 1-2 groups —OH; or (e)D1.

In some embodiments, D¹ is —CO₂R⁸.

In some embodiments, R⁶ and R⁷ are each independently H or —C₁₋₅alkyl.

In some embodiments, R⁸ is H or —C₁₋₅alkyl optionally substituted with1-7 halogens.

In some embodiments, d is 0, 1 or 2.

In some embodiments, d is 0 or 1.

In some embodiments, d is 0.

In some embodiments, Y¹, Y², and Y³ in Formula II are each —CH— or —N—.

In some embodiments, Y¹ and Y³ in Figure II are —CH—; and Y² is —CH— or—N—.

In some embodiments, A is A² wherein A² is phenyl or pyridyl optionallysubstituted with 1-3 groups independently selected from F, —CN, CH₃,CF₃, —OCH₃, and —OCF₃.

In some embodiments, R^(a1) is —CF₃.

In some embodiments, A³ is

wherein Z is —CH— or —N—;

X is 4-cyclohexyl-D¹, 4-phenyl-D¹ optionally substituted with 1-2 —CH₃groups, —CH₂CH₂D¹, cyclopentyl optionally substituted with 1-2 —OHgroups, HET(1), or isopropyl, wherein D¹ is —CO₂R⁸;

R⁸ is H or —CH₃;

R^(b) is —OCH₃ or halogen; and

e is an integer from 0-3.

In some embodiments, e is an integer from 0-2.

In some embodiments, e is an integer from 0-1.

In some embodiments, e is 0.

In some embodiments, A² is phenyl which is substituted with 2 groupsCF₃.

DEFINITIONS AND ABBREVIATIONS

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkylene” groups are alkyl groups that are difunctional rather thanmonofunctional. For example, methyl is an alkyl group and methylene(—CH₂—) is the corresponding alkylene group. Alkyl groups that are shownas difunctional are alkylene groups, even if they are referred to asalkyl groups.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated carbocyclic ring having from 3 to 8carbon atoms, unless otherwise stated. The term also includes acycloalkyl ring fused to an aryl group. Examples of cycloalkyl includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.“Cycloalkenyl” means a non-aromatic carbocyclic ring having one or moredouble binds.

“Aryl” when used to describe a substituent or group in a structure meansa monocyclic or bicyclic compound in which the rings are aromatic andwhich contain only carbon ring atoms. The term “aryl” can also refer toan aryl group that is fused to a cycloalkyl or heterocycle. Preferred“aryls” are phenyl and naphthyl. Phenyl is generally the most preferredaryl group.

“Heterocycle” or “heterocyclic” means a fully or partially saturated oraromatic cyclic compound containing 1 or more heteroatom groups whichmay be one or more of N, S, O, S(O), S(O)₂, or (N)R, and may have one ormore double bonds, where R is H or a substituent group. In general, whenheterocycles are defined herein, the definition will include the numberof ring members, the number of double bonds (if any), and the specificheteroatoms. The heterocycles in some cases will be aromatic, dependingon the number of double bonds (e.g. 6-membered ring with 3 doublebonds). Aromatic heterocycles are also referred to as “heteroaromatics.”S(O), S(O)₂, and N(R) are referred to as heteroatom groups, and eachheteroatom group is counted as one ring member, as is also the case forN, S, and O.

“Ac” is acetyl, which is CH₃C(═O)—.

“ACN” is acetonitrile.

“Benzoheterocycle” represents a phenyl ring fused to a heterocyclicring.

Examples include indole, benzofuran, 2,3-dihydrobenzofuran andquinoline.

“Boc” is tert-butoxycarbonyl.

“n-BuLi” is n-butyl lithium.

“Celite®” is a trade name for diatomaceous earth.

“DBU” is 1,8-diazabicyclo[5.4.0]undec-7-ene.

“D-Epoxone” is a commercial epoxidation catalyst.

“DIPEA” and “DIEA” are N,N-diisopropylethylamine.

“DCM” is dichloromethane.

“DIBAL-H” is diisobutylaluminum hydride.

“DMF” is N,N-dimethylformamide.

“DMAP” is 4-dimethylaminopyridine.

“DMSO” is dimethyl sulfoxide.

“DOPC” is 1,2-dioleoyl-sn-glycero-3-phosphocholine.

“EDTA” is ethylenediaminetetraacetic acid.

“EtOAc” is ethyl acetate.

“EtOH” is ethanol.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“HPLC” is high pressure liquid chromatography.

“IPA” is isopropyl alcohol.

“LiHMDS” is lithium hexamethyldisilazide.

“Me” represents methyl.

“MeCN” is acetonitrile.

“MeOH” is methanol.

“Ms” and “Mesylate” are methanesulfonate.

“NMP” is N-methyl-2-pyrrolidone.

“OXONE®” is a commercial persulfate oxidizing agent from DuPont.

“PEG” is poly(ethylene glycol).

“PTLC” is preparative thin layer chromatography.

“RBF” is a round bottom flask.

“Rochelle's salt” is potassium sodium tartrate.

“RT” and “r.t.” are abbreviations for room temperature.

“SFC” is supercritical fluid chromatography.

“SM” is starting material.

“TEA” is triethylamine.

“TFA” is trifluoroacetic acid.

“THF” is tetrahydrofuran.

“TLC” is thin layer chromatography.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s) and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of Formula I or II and apharmaceutically acceptable carrier.

The substituent “tetrazole” means a 2H-tetrazol-5-yl substituent groupand tautomers thereof.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

The compounds disclosed herein generally have at least one asymmetriccenter, and can thus occur as pure stereoisomers and as mixtures ofstereoisomers, including racemates, racemic mixtures, singleenantiomers, mixtures of enantiomers, diastereomeric mixtures andindividual diastereomers in all ratios. The invention includes allpossible enantiomers and diastereomers and mixtures of two or morestereoisomers, for example mixtures of enantiomers and/or diastereomers,in all ratios. Thus, enantiomers are a subject of the invention inenantiomerically pure form, both as levorotatory and as dextrorotatoryantipodes, in the form of racemates and in the form of mixtures of thetwo enantiomers in all ratios. In the case of a cis/trans isomerism theinvention includes both the cis form and the trans form as well asmixtures of these forms in all ratios. The preparation of individualstereoisomers can be carried out, if desired, by separation of a mixtureby customary methods, for example by chromatography or crystallization,by the use of stereochemically uniform starting materials for thesynthesis or by stereoselective synthesis. Optionally a derivatizationcan be carried out before a separation of stereoisomers. The separationof a mixture of stereoisomers can be carried out at an intermediate stepduring the synthesis of a compound of Formula I or II or it can be doneon a final racemic product. Absolute stereochemistry may be determinedby X-ray crystallography of crystalline products or crystallineintermediates which are derivatized, if necessary, with a reagentcontaining a stereogenic center of known configuration. Where compoundsof this invention are capable of tautomerization, all individualtautomers as well as mixtures thereof are included in the scope of thisinvention. The present invention includes all such isomers, as well assalts, solvates (which includes hydrates) and solvated salts of suchracemates, enantiomers, diastereomers and tautomers and mixturesthereof.

Different stereoisomers having the same 2-dimensional chemical structuremay have different levels of activity with respect to CETP inhibition,so that some stereoisomers may have higher activity than others. Thecompounds that are potent inhibitors of CETP may have utility inpatients for raising HDL-C, lowering LDL-C, treating dyslipidemia, andfor preventing, treating or delaying the onset of conditions that arerelated to atherosclerosis. Stereoisomers that have little or noactivity may have utility as research tools for better understandingCETP inhibition. All stereoisomers and mixtures of stereoisomers of theclaimed compounds thus have utility. The compounds of Formula I or IImay also occur as atropisomers (rotamers) due to hindered rotation,which may be observable by NMR spectroscopy, and in some cases may bestable enough with respect to conversion by bond rotation to otheratropisomers that they can be isolated and assayed.

Salts

When the compounds of Formula I contain one or more acidic or basicgroups the invention also includes the corresponding pharmaceuticallyacceptable salts. Thus, the compounds of Formula I which contain acidicgroups can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Examplesof such salts include but are not limited to sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of Formula I which contain one or more basicgroups, i.e. groups which can be protonated, can be used according tothe invention in the form of their acid addition salts with inorganic ororganic acids as, for example but not limited to, salts with hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroaceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofFormula I simultaneously contain acidic and basic groups in the moleculethe invention also includes, in addition to the salt forms mentioned,inner salts or betaines (zwitterions). Salts can be obtained from thecompounds of Formula I by customary methods which are known to theperson skilled in the art, for example by combination with an organic orinorganic acid or base in a solvent or dispersant, or by anion exchangeor cation exchange from other salts. The present invention also includesall salts of the compounds of Formula I which, owing to lowphysiological compatibility, are not directly suitable for use inpharmaceuticals but which can be used, for example, as intermediates forchemical reactions or for the preparation of pharmaceutically acceptablesalts.

Furthermore, compounds of the present invention may exist in one or moreamorphous forms and/or one or more crystalline forms, and as such allamorphous and crystalline forms and mixtures thereof of the compounds ofFormula I are intended to be included within the scope of the presentinvention. In addition, some of the compounds of the instant inventionmay form solvates with water (i.e., a hydrate) or common organicsolvents. Such solvates and hydrates, particularly the pharmaceuticallyacceptable solvates and hydrates, of the instant compounds are likewiseencompassed within the scope of this invention, along with un-solvatedand anhydrous forms.

It will be understood that, as used herein, references to the compoundsof Formula I and II and to the examples are meant to also include thepharmaceutically acceptable salts and prodrugs, where such salts andprodrugs are possible.

Prodrugs

Prodrugs, which are compounds that are converted to the compound ofFormula I or II as they are being administered to a patient or afterthey have been administered to a patient, are also compounds of formulaI or II in the sense that they provide the claimed pharmaceuticallyactive drug moiety to the patient.

Isotopes

In the compounds of Formula I and Formula II, the atoms may exhibittheir natural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula I and Formula II. For example, different isotopic formsof hydrogen (H) include protium (¹H) and deuterium (²H). Protium is thepredominant hydrogen isotope found in nature. Enriching for deuteriummay afford certain therapeutic advantages, such as increasing in vivohalf-life or reducing dosage requirements, or may provide a compounduseful as a standard for characterization of biological samples.Isotopically-enriched compounds within generic Formula I and II can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Utilities

The compounds disclosed herein, including pharmaceutically acceptablesalts thereof, are potent inhibitors of CETP. The compounds maytherefore be useful in treating mammalian patients, preferably humanpatients, having diseases and conditions that are treated by inhibitionof CETP.

One aspect of the present invention provides a method for treating orreducing the risk of developing a disease or condition that may betreated or prevented by inhibition of CETP by administering atherapeutically effective amount of the compound of Formula I or II to apatient in need of treatment. The patient is a human or mammal, but ismost often a human. A “therapeutically effective amount” is the amountof compound that is effective in obtaining a desired clinical outcome inthe treatment of a specific disease.

Diseases or conditions that may be treated with the compounds of FormulaI or Formula II, or which the patient may have a reduced risk ofdeveloping as a result of being treated with the compounds of Formula Ior Formula II, include: atherosclerosis, peripheral vascular disease,dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity, endotoxemia, and metabolic syndrome. There arereports in the scientific literature that suggest that inhibition ofCETP may have utility in preventing or slowing the development ofAlzheimer's disease. The compounds of Formula I and II may thereforehave utility in preventing or delaying the progression of Alzheimer'sdisease or other neurodegenerative diseases.

The compounds disclosed herein are particularly effective in raisingHDL-C and/or increasing the ratio of HDL-C to LDL-C. The compounds mayalso be effective in reducing LDL-C, and may be effective in treatingdyslipidemia. These changes in HDL-C and LDL-C may be beneficial intreating atherosclerosis, reducing or delaying the development ofatherosclerosis, reducing the risk of developing atherosclerosis, orpreventing atherosclerosis. The compounds disclosed herein may thus bebeneficial in treating atherosclerosis, reducing or delaying thedevelopment of atherosclerosis, reducing the risk of developingatherosclerosis, or preventing atherosclerosis.

Likely indications for atherosclerosis and dyslipidemia using thecompounds described herein are written below, where the drug product istitled “CETP inhibitor:”

Atherosclerosis. In patients at high risk of cardiovascular eventsbecause of existing coronary, cerebrovascular, or peripheral vasculardisease, CETP inhibitor co-administered with an HMG-CoA reductaseinhibitor is indicated to reduce the risk of coronary mortality,myocardial infarction, coronary revascularization procedures, ischemicstroke, and cardiovascular death.

Dyslipidemia. CETP inhibitor co-administered with a statin is indicatedto reduce elevated LDL-C, apolipoprotein B (ApoB), lipoprotein a(Lp(a)), non-HDL-C, and total cholesterol; and increase HDL-C andapolipoprotein A-1 (Apo A-1) in patients with mixed or primarydyslipidemia.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of the compoundsdescribed herein. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably the compound ofFormula I or II is administered orally.

When treating the diseases for which the compound of Formula I or II isindicated, generally satisfactory results are expected when the compoundof Formula I or II is administered at a daily dosage of from about 0.1milligram to about 1000 milligram in one dose daily or divided into morethan one dose per day.

Oral administration will usually be carried out using tablets. Examplesof doses in tablets include 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg,140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg,230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg,and 1000 mg. Other oral forms can also have the same dosages (e.g.capsules). A preferred dose is likely in the range of 50-200 mg.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise the compound of Formula I or II and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise the compound of Formula I or II or apharmaceutically acceptable salt as an active ingredient, as well as apharmaceutically acceptable carrier and optionally other therapeuticingredients. The term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic bases or acids and organic bases or acids. Apharmaceutical composition may also comprise a prodrug, or apharmaceutically acceptable salt thereof, if a prodrug is administered.A pharmaceutical composition may also consist essentially of thecompound of Formula I or II, or a pharmaceutically acceptable salt ofthe compound, and a pharmaceutically acceptable carrier, without othertherapeutic ingredients.

Pharmaceutical compositions may be formulated to be suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compound of Formula I or II can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compound can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

The compound of formula I or II may also be administered parenterally.Solutions or suspensions of the compound can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination Therapy

The compound of Formula I or II, including pharmaceutically acceptablesalts thereof, may be used in pharmaceutical combinations with otherdrugs that may also be useful in the treatment or amelioration of thediseases or conditions for which the compound of Formula I or II isuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially withthe compound of Formula I or II. When the compound of Formula I or II isused contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I or II is preferred. However, the combinationtherapy also includes therapies in which the compound of Formula I or IIand one or more other drugs are administered concomitantly, on the sameor different schedules. The drugs that are administered, whether aloneor in combination with other drugs, include the free-acid, free-base,and pharmaceutically acceptable salt forms, pro-drug forms (includingbut not limited to esters), and salts of pro-drugs of the medicinalagents where chemically possible

When oral formulations are used, the drugs may be combined into a singlecombination tablet or other oral dosage form, or the drugs may bepackaged together as separate tablets or other oral dosage forms. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compound of formula I or II and the other activeingredients may be used in lower doses than when each is used singly.Accordingly, the pharmaceutical compositions of the compound of formulaI or II include those that contain one or more other active ingredients,in addition to the compound of Formula I or II.

The compound of Formula I or II will likely be approved initially forcoadministration with a statin, which could be administered in the formof a fixed dose combination of the compound of formula I or II and astatin. Additional drugs may also be administered in combination withthe compound of Formula I or II and the statin, either bycoadministration or in a fixed dose combination. The compound of formulaI or II and the drugs that are administered with it may be administeredas pharmaceutically acceptable salts, as prodrugs, or otherwiseformulated for immediate release, extended release, or controlledrelease, as necessary.

Examples of statins that may be administered in combination with thecompound of Formula I or II include, but are not limited to, (i)simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® inlactone prodrug form and function as inhibitors after administration,and (ii) dihydroxy open ring acid HMG-CoA reductase inhibitors such asatorvastatin (particularly the calcium salt sold in LIPITOR®),rosuvastatin (particularly the calcium salt sold in CRESTOR®),pravastatin (particularly the sodium salt sold in PRAVACHOL®),fluvastatin (particularly the sodium salt sold in LESCOL®), andpitavastatin (particularly the calcium salt sold in LIVALO®), and (iii)other statins that may yet be developed. Preferred statins forcombination therapy include atorvastatin, rosuvastatin, and simvasatin,as described above.

Cholesterol absorption inhibitors, and particularly ezetimibe (ZETIA®),as well as other cholesterol absorption inhibitors, such as stanolesters, beta-sitosterol, sterol glycosides such as tiqueside, and otherazetidinones, may be administered with the compound of Formula I or II,generally with a statin, as described above. The preferred cholesterolabsorption inhibitor is ezetimibe. Combinations of the compound offormula I or II with a statin and a cholesterol inhibitor, such asezetimibe, are also contemplated. Preferred 3-component combinationsinclude combinations of the compound of formula I or II withsimvastatin, atorvastatin, or rosuvastatin in combination withezetimibe, where the statins may be salt forms or prodrugs as describedabove. The combination of simvastatin with ezetimibe is currentlymarketed as VYTORIN®.

Other cholesterol reducing drugs that may be coadministered with thecompound of formula I or II in addition to HMG-CoA reductase inhibitors(statins) and cholesterol absorption inhibitors include (i) bile acidsequestrants, as for example cholestyramine, colestipol,dialkylaminoalkyl derivatives of a cross-linked dextran, Colestid®, andLoCholest®, (ii) niacin and related compounds, such as nicotinylalcohol, nicotinamide, and nicotinic acid or a salt thereof, in animmediate release or extended release form, which may optionally be inthe forme of a combination with a DP-1 antagonist, such as laropiprant(TREDAPTIVE®); (iii) PPARα agonists, such as gemfibrozil and fenofibricacid derivatives (fibrates), including clofibrate, fenofibrate,bezafibrate, ciprofibrate, and etofibrate, (iv) acyl CoA:cholesterolacyltransferase (ACAT) inhibitors, such as avasimibe and melinamide, andincluding selective ACAT-1 and ACAT-2 inhibitors and dual inhibitors,(v) phenolic anti-oxidants, such as probucol, (vi) microsomaltriglyceride transfer protein (MTP)/ApoB secretion inhibitors, (vii)anti-oxidant vitamins, such as vitamins C and E and beta carotene,(viii) thyromimetics, (ix) LDL (low density lipoprotein) receptorinducers, (x) platelet aggregation inhibitors, for example glycoproteinIIb/IIIa fibrinogen receptor antagonists and aspirin, (xi) vitamin B12(also known as cyanocobalamin), (xii) folic acid or a pharmaceuticallyacceptable salt or ester thereof, such as the sodium salt and themethylglucamine salt, (xiii) FXR and LXR ligands, including bothinhibitors and agonists, (xiv) agents that enhance ABCA1 geneexpression, (xv) ileal bile acid transporters, and (xvi) niacin receptoragonists (e.g. acipimox and acifran) and partial agonists.

Finally the compound of formula I or II can be combined with compoundsthat are useful for treating other diseases, such as diabetes,hypertension and obesity, as well as other anti-atheroscleroticcompounds. Such combinations may be used to treat one or more of suchdiseases as diabetes, obesity, atherosclerosis, and dyslipidemia, ormore than one of the diseases associated with metabolic syndrome. Thecombinations may exhibit synergistic activity in treating thesediseases, allowing for the possibility of administering reduced doses ofactive ingredients, such as doses that otherwise might besub-therapeutic.

Examples of other active ingredients that may be administered incombination with a compound of formula I or II include, but are notlimited to, compounds that are primarily anti-diabetic compounds,including:

(a) PPAR gamma agonists and partial agonists, including glitazones andnon-glitazones (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone,balaglitazone, netoglitazone, T-131, LY-300512, LY-818, and compoundsdescribed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO2004/066963);

(b) biguanides such as metformin, phenformin, and pharmaceuticallyacceptable salts thereof, in particular metformin hydrochloride andextended release formulations thereof, such as Glumetza™, Fortamet™, andGlucophageXR™;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors, such asISIS-113715 and TTP814;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors, including sitagliptin,vildagliptin, saxagliptin, alogliptin, linagliptin, dutogliptin,teneligliptin, MK-3102, and gemigliptin;

(e) insulin or insulin mimetics, such as for example insulin lispro,insulin glargine, insulin detemir, insulin glulisine, insulin degludec,SBS1000, insulin zinc suspension, and oral and inhalable formulations ofinsulin and insulin analogs;

(f) sulfonylureas, such as tolbutamide, glipizide, glimepiride,acetohexamide, chlorpropamide, glibenclamide, and related materials;

(g) α-glucosidase inhibitors (such as acarbose, adiposine; camiglibose;emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin);

(h) PPARα/γ dual agonists, such as muraglitazar, tesaglitazar,farglitazar, and naveglitazar;

(i) PPARδ agonists such as GW501516 and those disclosed in WO97/28149;

(j) glucagon receptor antagonists;

(k) GLP-1; GLP-1 derivatives; GLP-1 mimetics, GLP-1 analogs, and GLP-1receptor agonists, such as exendins, e.g. exenatide (BYETTA),dulaglutide, semaglutide, albiglutide, liraglutide, lixisenatide, andtaspoglutide, including intranasal, tranxsdermal, and once weeklyfomulations thereof, and oxyntomodulin analogs and derivatives, andnon-peptidyl GLP-1 receptor agonists;

(l) GIP-1;

(m) amylin and amylin analogs (e.g. pramlintide);

(n) Non-sulfonylurea insulin secretagogues, such as the meglitinides(e.g. glimepiride, mitiglinide, meglitinide, nateglinide, andrapeglinide); and

(o) leptin and leptin derivatives and agonists.

Preferred combinations with antidiabetic compounds include combinationsof the compounds disclosed herein with DP-IV inhibitors (sitagliptin,vildagliptin, saxagliptin, alogliptin, linagliptin, dutogliptin,teneligliptin, omarigliptin, and gemigliptin), combinations withbiguanides, and combinations with both a DP-IV inhibitor and abiguanide. The preferred DP-IV inhibitor is sitagliptin, and thepreferred biguanide is metformin in the formulations and salt formsdescribed above.

Other active ingredients that may be used in combination with thecompound of formula I or II include antiobesity compounds, including5-HT(serotonin) inhibitors, neuropeptide Y5 (NPY5) inhibitors,melanocortin 4 receptor (Mc4r) agonists, cannabinoid receptor 1 (CB-1)antagonists/inverse agonists, and β₃ adrenergic receptor agonists. Theseare listed in more detail later in this section.

These other active ingredients also include active ingredients that areused to treat inflammatory conditions, such as aspirin, non-steroidalanti-inflammatory drugs, glucocorticoids, azulfidine, and selectivecyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib,rofecoxib, and Bextra.

Antihypertensive compounds may also be used advantageously incombination therapy with the compound of formula I or II. Examples ofantihypertensive compounds that may be used with the compound of formulaI or II include thiazide-like diuretics, e.g., hydrochlorothiazide (HCTZor HCT); angiotensin converting enzyme inhibitors (e.g, alacepril,benazepril, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril); dual inhibitors of angiotensin converting enzyme (ACE)and neutral endopeptidase (NEP) such as omapatrilat, sampatrilat andfasidotril; angiotensin II receptor antagonists, also known asangiotensin receptor blockers or ARBs, which may be in free-base,free-acid, salt or pro-drug form, such as azilsartan, e.g., azilsartanmedoxomil potassium (EDARBI®), candesartan, e.g., candesartan cilexetil(ATACAND®), eprosartan, e.g., eprosartan mesylate (TEVETAN®), irbesartan(AVAPRO®), losartan, e.g., losartan potassium (COZAAR®), olmesartan,e.g, olmesartan medoximil (BENICAR®), telmisartan (MICARDIS®), valsartan(DIOVAN®), and any of these drugs used in combination with athiazide-like diuretic such as hydrochlorothiazide (e.g., HYZAAR®,DIOVAN HCT®, ATACAND HCT®), etc.); potassium sparing diuretics such asamiloride HCl, spironolactone, epleranone, triamterene, each with orwithout HCTZ; carbonic anhydrase inhibitors, such as acetazolamide;neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon);aldosterone antagonists; aldosterone synthase inhibitors; renininhibitors (e.g. urea derivatives of di- and tri-peptides (See U.S. Pat.No. 5,116,835), amino acids and derivatives (U.S. Pat. Nos. 5,095,119and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S.Pat. No. 5,114,937), di- and tri-peptide derivatives (U.S. Pat. No.5,106,835), peptidyl amino diols (U.S. Pat. Nos. 5,063,208 and4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Pat.No. 5,089,471); also, a variety of other peptide analogs as disclosed inthe following U.S. Pat. Nos. 5,071,837; 5,064,965; 5,063,207; 5,036,054;5,036,053; 5,034,512 and 4,894,437, and small molecule renin inhibitors(including diol sulfonamides and sulfinyls (U.S. Pat. No. 5,098,924),N-morpholino derivatives (U.S. Pat. No. 5,055,466), N-heterocyclicalcohols (U.S. Pat. No. 4,885,292) and pyrolimidazolones (U.S. Pat. No.5,075,451); also, pepstatin derivatives (U.S. Pat. No. 4,980,283) andfluoro- and chloro-derivatives of statone-containing peptides (U.S. Pat.No. 5,066,643); enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES8891; SQ 34017; aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635); endothelin receptorantagonists; vasodilators (e.g. nitroprusside); calcium channel blockers(e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine,gallopamil, niludipine, nimodipine, nicardipine, bepridil, nisoldipine);potassium channel activators (e.g., nicorandil, pinacidil, cromakalim,minoxidil, aprilkalim, loprazolam); sympatholitics; beta-adrenergicblocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol,carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol,sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazocin,prazocin or alpha methyldopa); central alpha adrenergic agonists;peripheral vasodilators (e.g. hydralazine); and nitrates or nitric oxidedonating compounds, e.g. isosorbide mononitrate.

Preferred antihypertensives that may be used in combination with theCETP inhibitors disclosed herein include one or more of an angiotensinII antagonist (losartan), an ACE inhibitor (enalapril or captopril), andhydrochlorothiazide.

Anti-obesity compounds may be administered in combination with thecompounds of Formula I or Formula II, including: (1) growth hormonesecretagogues and growth hormone secretagogue receptoragonists/antagonists, such as NN703 and hexarelin; (2) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands,such as cannabinoid CB₁ receptor antagonists or inverse agonists, suchas rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A(Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4)anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine,phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such asAD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344,L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, ZenecaD7114, and SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat(Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin,teasaponin, and diethylumbelliferyl phosphate; (7) neuropeptide Y1antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897,CP-671906, and GI-264879A; (8) neuropeptide Y5 antagonists, such asGW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662,FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170,SR-120562A, SR-120819A and JCF-104; (9) melanin-concentrating hormone(MCH) receptor antagonists; (10) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda); (11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;(12) orexin-1 receptor antagonists, such as SB-334867-A; (13)melanocortin agonists, such as Melanotan II; (14) other Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (15) 5HT-2 agonists; (16) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, and R-1065; (17) galaninantagonists; (18) CCK agonists; (19) CCK-A (cholecystokinin-A) agonists,such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131;(20) GLP-1 agonists; (21) corticotropin-releasing hormone agonists; (22)histamine receptor-3 (H3) modulators; (23) histamine receptor-3 (H3)antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, and GT2394 (Gliatech); (24) β-hydroxysteroid dehydrogenase-1 inhibitors (11β-HSD-1 inhibitors), such as BVT3498 and, BVT 2733, (25) PDE (phosphodiesterase) inhibitors, such astheophylline, pentoxifylline, zaprinast, sildenafil, amrinone,milrinone, cilostamide, rolipram, and cilomilast; (26)phosphodiesterase-3B (PDE3B) inhibitors; (27) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (28) ghrelin receptor antagonists; (29) leptin, includingrecombinant human leptin (PEG-OB, Hoffman La Roche) and recombinantmethionyl human leptin (Amgen); (30) leptin derivatives; (31) BRS3(bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide; (32) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (33) CNTFderivatives, such as axokine (Regeneron); (34) monoamine reuptakeinhibitors, such as sibutramine; (35) UCP-1 (uncoupling protein-1, 2, or3) activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; (36) thyroid hormone β □agonists, suchas KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthase) inhibitors, suchas Cerulenin and C75; (38) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (39) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(40) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (41) glucocorticoidantagonists; (42) acyl-estrogens, such as oleoyl-estrone; (43)dicarboxylate transporter inhibitors; (44) peptide YY, PYY 3-36, peptideYY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C,(45) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (46) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP); (47) Neuropeptide Y1 (NPY1)antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906,and GI-264879A; (48) Opioid antagonists, such as nalmefene (Revex®),3-methoxynaltrexone, naloxone, and naltrexone; (49) glucose transporterinhibitors; (50) phosphate transporter inhibitors; (51) 5-HT (serotonin)inhibitors; (52) beta-blockers; (53) Neurokinin-1 receptor antagonists(NK-1 antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex;(57) clortermine; (58) cyclexedrine; (59) dextroamphetamine; (60)diphemethoxidine, (61) N-ethylamphetamine; (62) fenbutrazate; (63)fenisorex; (64) fenproporex; (65) fludorex; (66) fluminorex; (67)furfurylmethylamphetamine; (68) levamfetamine; (69) levophacetoperane;(70) mefenorex; (71) metamfepramone; (72) methamphetamine; (73)norpseudoephedrine; (74) pentorex; (75) phendimetrazine; (76)phenmetrazine; (77) picilorex; (78) phytopharm 57; (79) zonisamide, (80)aminorex; (81) amphechloral; (82) amphetamine; (83) benzphetamine; and(84) chlorphentermine.

The combination therapies described above which use the compounds ofFormula I or Formula II may also be useful in the treatment of themetabolic syndrome. According to one widely used definition, a patienthaving metabolic syndrome is characterized as having three or moresymptoms selected from the following group of five symptoms: (1)abdominal obesity; (2) hypertriglyceridemia; (3) low high-densitylipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevatedfasting glucose, which may be in the range characteristic of Type 2diabetes if the patient is also diabetic. Each of these symptoms isdefined clinically in the Third Report of the National CholesterolEducation Program Expert Panel on Detection, Evaluation and Treatment ofHigh Blood Cholesterol in Adults (Adult Treatment Panel III, or ATPIII), National Institutes of Health, 2001, NIH Publication No. 01-3670.Patients with metabolic syndrome have an increased risk of developingthe macrovascular and microvascular complications that are listed above,including atherosclerosis and coronary heart disease. The combinationsdescribed above may ameliorate more than one symptom of metabolicsyndrome concurrently (e.g. two symptoms, three symptoms, four symptoms,or all five of the symptoms).

Assays Protocol: Scintillation Proximity Assay (SPA) for CETP Activity

First, low density lipoprotein (LDL) (Meridian) was biotinylated byincubating LDL with biotin for 1 hour on ice, after which it wasdialyzed to remove free biotin. Then compounds at varying concentrationswere incubated with 15 nM CETP (reagent production group, In VitroPharmacology, MRL Rahway) and 50 ug/ml of the biotinylated LDL in 50 mMHEPES, 150 mM NaCl, pH 7.4, for 1 hour at 37° C. The reaction wasstarted by adding ³H-cholesterol ester high density lipoprotein (HDL)(American Radiochemicals Corp) at a concentration of 0.6 nM. Thereaction proceeded for 2 hours at 37° C., after which time it wasquenched by the addition of 12% acetic acid. PVT streptavadin-coatedscintillation proximity beads, which had been brought to roomtemperature, were then added at a concentration of 4 mg/ml. The assaywas then mixed and counted after one half hour in a Microbeta platereader.

In Vitro Radioactive Assays of CETP-Catalyzed CE and TG Transfer (RTAAssay)

Reagents and sources are: [3H] cholesteryl oleate (GE #TRK.886), [3H]Triolein (Perkin-Elmer NET-431), Butylated hydroxyl toluene (Aldrich,#D4740-4), DOPC (Sigma, # P6354), Sodium Bromide (Fisher scientific#S255-500), PEG 8000 (Fisher, #BP233-1), and human HDL (Intracel Corp#RP-036).

An in vitro assay for determining IC₅₀'s to identify compounds thatinhibit CETP transfer activity is performed based on a modification of apublished method (Morton and Zilversmit, (1981) A plasma inhibitor oftriglyceride and cholesteryl ester transfer activities, J. Biol. Chem.256(23), 11992-11995). The ability of inhibitors to alter CETP activityis performed using two different assays: one using recombinant CETP andone using an endogenous plasma source of CETP. Both assays measure thetransfer of [3H] cholesteryl oleate or [3H] triolein from exogenous LDLto HDL.

Radiolabeled donor particles are generated by first combining 100 μl of200 μM butylated hydroxyl toluene in CHCl₃, 216 μL of 21.57 mM DOPC inEtOH, and either 500 μCi [3H]-triolein (Perkin Elmer #NET-431) or 500μCi [3H]-cholesteryl oleate (GE #TRK886) in a glass tube. Reagents aremixed, dried under nitrogen, and then resuspended in 2 mL of 50 mM Tris,27 μM EDTA at pH 7.4. After a brief vortex, the solution is sonicateduntil clear and mixed with 20 mL of fresh human serum. The mixture isincubated overnight at 37° C. The [3H] labeled LDL substrate isseparated at 1.063 g/ml density by sequential ultracentrifugal flotationin NaBr according to the method of Havel, Eder, et al., 1955, andChapman, Goldstein, et al., 1981. Once isolated the particles aredialyzed 3× in CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA).Human HDL is purchased from Intracel and used as the acceptor particles.

Transfer assays are performed in a 96-well v-bottom polypropylene plate.For the RTA using recombinant CETP (2% RTA), an assay cocktail isprepared with the final concentrations 128 μg/mL HDL, 20 nM rCETP, 2%human serum, and 1×CETP buffer. 1 μL of each test compound diluted inDMSO is added to 47 μL of assay cocktail per well and incubated at 37°C. for 1 hour. To initiate the transfer reaction, 2 μL radiolabeled LDLis added. After an additional 60 min of incubation at 37° C., thetransfer action is terminated by precipitation of LDL with an equalvolume of 20% W/V PEG 8000. The plates are centrifuged at 2000 rpm for30 minutes at 4° C. A 40 μL aliquot of the HDL-containing supernatant istransferred to a Packard Optiplate™ with 200 μL of MicroScint™ 20. Aftermixing, plates are counted by liquid scintillation. Counts present inthe supernatant for blanks (wells containing only HDL acceptor, CETPbuffer and DMSO) are subtracted from those containing test compounds andused to correct for non-specific transfer.

For the transfer assay using endogenous CETP from serum (95% RTA), thesame procedure is used except that human serum is added such that afinal concentration of serum of 95% of the total assay volume isachieved, yielding a concentration of approximately 15 nM endogenousCETP in the assay. This is then combined with HDL and CETP buffer andthe reaction proceeds as above and is terminated as described.

Comparison of the counts of samples with inhibitors to an uninhibited(DMSO only) positive control yield a percent inhibition. A plot ofpercent inhibition vs. log of inhibitor concentration, fit to aSigmoidal 4 parameter equation is used to calculate IC50.

EXAMPLES

The following schemes and examples are provided so that the inventionwill be more fully appreciated and understood. These examples areillustrative and are not to be construed as limiting the invention inany way. The claims appended hereto define the scope of the invention.

Starting materials are commercially available or are made using knownprocedures or as shown below. The examples may be synthesized using thegeneral schemes provided below. Synthetic intermediates for making thecompounds are made as described below. The data reported for theexamples below were generally obtained using the RTA assay in 95% humanserum. The IC50's for the examples using this assay are in the range ofabout 25-300 nM. Preferred compounds have an IC50 less than about 200nM. More preferred compounds have an IC50 less than about 100 nM. Whencompounds of Formula I or Formula II are mentioned herein, suchcompounds include compounds defined generically by Formula I or II andalso the specific examples disclosed herein.

General Synthetic Schemes

The schemes and examples are illustrative and are not to be construed aslimiting the invention.

Benzyl((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamatewas synthesized according to a published procedure (Ying et al., J. Org.Chem., 2006, 71, 840-843). After switching the protecting group from Cbzto Boc, the secondary alcohol was converted to a leaving group(mesylate), which was displaced with potassium thioacetate. Afterdeprotection, the resulting aminothiol was cyclized with triphosgene togive the thiazolidinone compound (intermediate A1). Intermediate A1 wasalkylated to give intermediate A2.

Intermediate A1

(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one

Step 1:

To benzyl((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate(3.0 g, 7.12 mmol) in ethanol (100 mL) was added palladium on carbon(0.379 g, 0.356 mmol). The system was stirred at room temperature undera hydrogen atmosphere at 50 psi for 1.5 hours. The reaction was filteredand the filtrate was concentrated. Crude(2S)-2-amino-1-(3,5-bis(trifluoromethyl)phenyl)propan-1-ol was carriedforward without further purification. MS ESI calc'd. for C₁₁H₁₁F₆NO[M+H]⁺ 288.2. found 288.0.

Step 2:

(2S)-2-Amino-1-(3,5-bis(trifluoromethyl)phenyl)propan-1-ol (2 g, 6.96mmol) in acetonitrile (50 ml) was cooled to 0° C., and DIPEA (2.2 ml,12.5 mmol) was added, followed by Boc₂O (1.62 ml, 6.96 mmol). Thereaction was warmed to r.t. and stirred for 3 hours. The reaction wasdiluted with 50% EtOAc in hexane, then was washed with water and thenbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Crude product was purified by column chromatography toyield tert-butyl((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate. The crude material was judged to have a 4:1 diastereomericratio by ¹H NMR analysis.

Step 3:

To a solution of tert-butyl((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate(2.0 g, 5.16 mmol) and triethylamine (1.15 ml, 8.26 mmol) at 0° C. inDCM (20 ml) was added methanesulfonyl chloride (0.48 ml, 6.2 mmol). Thereaction was stirred at 0° C. for 1 hour and then was quenched with asaturated solution of NH₄Cl. The organic layer was washed with water andbrine, dried over Na₂SO₄, and concentrated. The product was purified bycolumn chromatography to yield(2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propylmethanesulfonate. The crude material was judged to have a 9:1diastereomeric ratio by ¹H NMR analysis. ¹H NMR (500 MHz, CDCl₃): δ 7.91(s, 1H); δ 7.87 (s, 0.1H); δ 7.84 (s, 2H); 5.73 (d, J=4.3 Hz, 1H); δ5.21 (d, J=7.0 Hz, 0.1H); δ 4.58 (s, 1H); 4.18 (br s, 1H); 3.02 (s, 3H);1.39 (s, 9H); 1.25 (d, J=6.9 Hz, 3H).

Step 4:

(2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propylmethanesulfonate (1.0 g, 2.15 mmol) and potassium ethanethioate (0.736g, 6.45 mmol) were combined in DMF (5 ml). The reaction was stirred atroom temperature for 5 hours under a N₂ atmosphere. The reaction wasdiluted with 30% EtOAc in hexane, washed with water, then brine, driedover Na₂SO₄, filtered and concentrated. The compound was purified bycolumn chromatography to yieldS-((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl)ethanethioate. ¹H NMR (500 MHz, CDCl₃): δ 7.84 (s, 2H); 7.79 (s, 1H);4.91 (s, 1H); 4.51 (s, 1H); 4.21 (s, 1H); 2.40 (s, 3H); 1.38 (s, 9H);1.19 (d, J=6.9 Hz, 3H).

Step 5:

TheS-((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl)ethanethioate (580 mg, 1.30 mmol) in MeOH (30 ml) was thoroughlydegassed and degassed NaOH solution (1.43 ml, 1.43 mmol) was addeddropwise. The reaction was stirred at r.t. for 30 minutes under a N₂atmosphere to yield tert-butyl((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-mercaptopropan-2-yl)carbamate.To the same reaction was added TFA (0.502 ml, 6.51 mmol), and thereaction mixture was stirred for 10 min., and then MeOH was removed. Theresidue was redissolved in DCM (6.0 ml), TFA (50% in DCM) (4.0 ml, 26.0mmol) was added, and the mixture was stirred for 40 minutes at roomtemperature to yield(2S)-2-amino-1-(3,5-bis(trifluoromethyl)phenyl)propane-1-thiol. Thereagents were removed, and the residue was dried under high vacuum. Thereaction was dissolved in DCM (12.00 ml), degassed, and was cooled to 0°C. DIPEA (0.682 ml, 3.91 mmol) was added, followed by triphosgene (155mg, 0.521 mmol), which was predissolved in DCM (6.0 ml) under N₂atmosphere dropwise. The reaction was stirred for 30 minutes to yield((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one.The reaction was diluted with DCM, washed with 1N NaHCO₃ solution, thenbrine. The organic layer was then dried over Na₂SO₄, filtered, andconcentrated to yield(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one. ¹HNMR (500 MHz, CDCl₃): δ 7.90 (s, 1H); 7.86 (s, 2H); 5.00 (d, J=6.9 Hz,1H); 4.41-4.42 (m, 1H); 0.99 (d, J=6.6 Hz, 3H).

Intermediate A2

(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-bromo-5-(trifluoromethyl)benzyl)-4-methylthiazolidin-2-one

Step 1:

To a solution of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one (50mg, 0.152 mmol) in THF (1 ml) was added NaH (7.59 mg, 0.190 mmol) at−20° C. 30 Minutes later, a solution of2-bromo-5-(trifluoromethyl)benzyl methanesulfonate (50.6 mg, 0.152 mmol)in THF (0.5 ml) was added. Stirring of the reaction continued for 1hour. A crude NMR spectrum showed only 25% product formation. Thereaction temperature was increased to −10° C., and stirring wascontinued for another 1 h. The reaction mixture was left in the freezerunder N₂ atmosphere overnight. NMR and LCMS indicated around a 65%conversion to the desired isomer, with no undesired epimerized product.The reaction was cooled to −10° C., and additional NaH (2.429 mg, 0.061mmol) was added. Stirring of the reaction mixture was continued for 20minutes. 2-Bromo-5-(trifluoromethyl)benzyl methanesulfonate (20.2 mg,0.061 mmol) was added, and the reaction was continued for another 2hours at −10° C. The reaction mixture was quenched with ice water, andthe mixture was diluted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by PTLC by using 35% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃):δ 7.90 (s, 1H); 7.85 (s, 2H); 7.76 (d, J=8.3 Hz, 1H); 7.59 (s, 1H); 7.48(d, J=8.5 Hz, 1H); 5.15 (d, J=7.0 Hz, 1H); 5.02 (d, J=16.0 Hz, 1H); 4.45(d, J=16.0 Hz, 1H); 4.10-4.11 (m, 1H); 0.97 (d, J=6.5 Hz, 3H).

Intermediate A3

(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-4-methylthiazolidin-2-one

Step 1:

A solution of NaH (18 mg, 0.46 mmol) in THF (2.0 ml) was cooled to −20°C. To this was added a solution of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one(100 mg, 0.304 mmol) in THF (1.0 ml) dropwise at the same temperature.The reaction was allowed to warm to −10° C. over 1 hour. A solution of(3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (106mg, 0.364 mmol) in THF (1.0 ml) was added via syringe. Stirring of thereaction was continued at −10° C. for 5 hours. The reaction was quenchedby addition of ice water and diluted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecompound was purified by column chromatography to yield(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((3-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-4-methylthiazolidin-2-one.¹H NMR (500 MHz, CDCl₃): δ 7.91 (d, J=8.2 Hz, 1H); 7.89 (s, 1H); 7.85(s, 2H); 7.64 (d, J=8.3 Hz, 1H); 5.36 (d, J=17.5 Hz, 1H); 5.24 (d, J=6.9Hz, 1H); 4.54-4.55 (m, 1H); 4.37 (d, J=17.5 Hz, 1H); 0.99 (d, J=6.6 Hz,4H).

Preparation of Intermediate B begins with formation of a tert-butylester which is then subjected to a Miyuara coupling to obtain thecorresponding boronic ester. Suzuki coupling with a commerciallyavailable 5-bromo-3-chloro-2-methoxypyridine yields the coupledchloride. A second Miyaura coupling provides the desired boronic esterIntermediate B.

Intermediate B1

tert-butyl4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate

Step 1:

To a 250 mL RBF was added 4-bromo-3-methylbenzoic acid (10 g, 46.5mmol), DMAP (8.52 g, 69.8 mmol), and tert-butyl alcohol (100 mL).Di-tert-butyl dicarbonate (12.96 mL, 55.8 mmol) was added via a syringeto the solution, which caused vigorous bubbling, foaming and the loss ofsome material. The remaining reaction mixture was heated at 70° C.overnight. The reaction was cooled to room temperature, and thevolatiles were removed under reduced pressure. Crude material wasdiluted with ethyl acetate:hexanes (1:4, 200 mL) and was washedsequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammoniumchloride (2×100 mL). The organics were dried over sodium sulfate,filtered, and concentrated before purification by column chromatography.tort-Butyl 4-bromo-3-methylbenzoate was isolated as a colorless oil. ¹HNMR (500 MHz, CDCl₃) δ 7.87 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.60 (d,J=8.2 Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).

Step 2:

To a 250 mL RBF was added 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.317 g, 0.487 mmol), tert-butyl4-bromo-3-methylbenzoate (6.6 g, 24.34 mmol), bis(pinacolato)diboron(7.42 g, 29.2 mmol), potassium acetate (5.97 g, 60.9 mmol), and dioxane(25 mL). The system was flushed with nitrogen and was heated to 125° C.overnight. The reaction was then cooled to room temperature and wasdiluted with ethyl acetate:hexanes (1:9, 120 mL), and was then waswashed sequentially with water (150 mL) and brine (50 mL). The organicswere dried over sodium sulfate, filtered, and concentrated beforepurification by column chromatography. tert-Butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate wasisolated as a crystalline solid. ¹H NMR indicated it to be about 70%pure. ¹H NMR (500 MHz, CDCl₃) δ 7.8 (m, 3H), 2.60 (s, 3H), 1.58 (s, 9H),1.39 (s, 12H).

Step 3:

To a 250 mL RBF was added 5-bromo-3-chloro-2-methoxypyridine (1.5 g),tribasic potassium phosphate (2.86 g, 13.5 mmol),bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct(0.275 g, 6.74 mmol), tert-butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.27g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealedand was stirred at 80° C. overnight. The reaction was cooled to roomtemperature, diluted with ethyl acetate, washed with water, filtered,and concentrated. The resultant residue was purified by columnchromatography to yield tert-butyl4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate. MS ESI calc'd. forC₁₈H₂₁C₁NO₃ [M+H]+ 334.1. found 334.0.

Step 4:

To a 250 mL RBF was added tert-butyl4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (4.5 g, 13.5 mmol),bis(pinacolato)diboron (6.85 g, 27.0 mmol), potassium acetate (3.97 g,40.4 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.212 g, 0.27 mmol) followed by anhydrous dioxane (50 mL). The systemwas evacuated and backfilled with nitrogen (3×) and was heated to 120°C. for 2 hours. The mixture was cooled, filtered over Celite (ethylacetate wash) and was concentrated. The residue was purified by columnchromatography to afford tert-butyl4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoateas a solid. MS ESI calc'd. for C₂₄H₃₃BNO₅ [M+H]+ 426.2. found 426.0.

EXAMPLES General Synthetic Schemes

Compounds of the present invention can be synthesized according to thegeneral schemes outlined below. Syntheses of representative examplesfollow. The starting materials in the schemes are commercially availableor are readily synthesized by a person skilled in the art. The schemesand examples are illustrative and are not to be construed as limitingthe invention.

In accordance with Scheme 1, a cross-coupling reaction betweenIntermediate A and an appropriately functionalized boronic acid/ester(intermediate B) provides compounds of the general formula (I). Some ofthe intermediates B are synthesized according to published procedures inWO 2012/058187, for example Intermediates 2 and 7 on pages 38 and 46. Incases where an ester group is present in the final compound, asaponification or hydrolysis may subsequently be carried out to generatethe acid.

Example 1

2″-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxothiazolidin-3-yl)methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-[1,1′:3′,1″-terphenyl]-4-carboxylicacid

In a microwave vial was placed(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-bromo-5-(trifluoromethyl)benzyl)-4-methylthiazolidin-2-one(20 mg, 0.035 mmol) in N,N-Dimethylacetamide (0.5 ml). The mixture wasdegassed with N₂, thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.78 mg, 3.53 μmol) was added, followed by potassium phosphate tribasic(0.035 ml, 0.071 mmol) and then(4′-(tert-butoxycarbonyl)-4-methoxy-2′-methyl-[1,1′-biphenyl]-3-yl)boronicacid (18.13 mg, 0.053 mmol) (synthesized according to the procedurereported in WO 2012/058187) under a N₂ atmosphere. The resulting mixturewas stirred at 80° C. for 1 hour. The reaction was diluted with 50%EtOAc in hexane, then was washed with satd. NH₄Cl, then brine, and thenthe organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was dissolved in 50% TFA in DCM and was stirred at r.t. for 45min. The reagents were removed, the residue was dissolved in ACN:H₂O(3:1) mixture, and was purified by a reverse phase purification system.¹H NMR (500 MHz, CDCl₃, 1:1 mixture of atropisomers): δ 8.02 (d, J=12.5Hz, 1H, contains protons of two atropisomers), 7.95 (d, J=8.5 Hz, 1H,contains protons of two atropisomers), 7.84 (d, J=10.5 Hz, 1H, containsprotons of two atropisomers), 7.75 (s, 1H), 7.65 (m, 3H), 7.44 (m, 2H),7.36 (d, J=7.5 Hz, 0.5H), 7.32 (d, J=7.5 Hz, 0.5H), 7.11 (d, J=3.5 Hz,0.5H), 7.10 (d, J=3.5 Hz, 0.5H), 5.18 (d, J=15.5 Hz, 0.5H), 5.04 (d,J=15.5 Hz, 0.5H), 4.95 (d, J=7.0 Hz, 0.5H), 4.84 (d, J=7.5 Hz, 0.5H),4.16 (d, J=15.5 Hz, 0.5H), 3.92 (d, 0.5H, one of the doublet peaksmerged with a methoxy peak), 3.90 (s, 3H), 3.86 (s, 3H), 3.79 (m, 1H),2.42 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.63(d, J=6.5 Hz, 3H). MS ESI calc'd. for C₃₅H₂₆F₉NO₄ [M+H]+ 727.14. found728.0. RTA (95% HS): 62 nM.

The following compounds in Table 1 were prepared according to generalScheme 1 using the procedure outlined in Example 1 utilizingcommercially available or known halides or boronic acids/esters and theprocedures described above.

TABLE 1 Example Structure IUPAC Name IC50 nM Exact Mass 2

3′-[2-({(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3-thiazolidin-3- yl}methyl)-6- (trifluoromethyl)pyridin-3-yl]-4′-methoxy-2- methylbiphenyl-4- carboxylic acid 39 Calc′d 729,found 729.1 3

4-[2′-({(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo1,3-thiazolidin-3- yl}methyl)-2-methoxy- 6′-(trifluoromethyl)-3,3′-bipyridin-5-yl]-3- methylbenzoic acid 106 Calc′d 730, found 730.2 4

3-{3-[2-({(4S,5R)-5- [3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3-thiazolidin-3- yl}methyl)-6- (trifluoromethyl) pyridin-3-yl]-4-methoxyphenyl} propanoic acid 300 Calc′d 667, found 667.0 5

4-[2′-({(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3-thiazolidin-3- yl}methyl)-2-methoxy- 6′-(trifluoromethyl)-3,3′-bipyridin-5-yl]- 3,5-dimethylbenzoic acid 25 Calc′d 744, found744.1 6

trans-4-{3-[2- ({(4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-4-methyl-2-oxo- 1,3-thiazolidin-3- yl}methyl)-6-(trifluoromethyl) pyridin-3-yl]-4- methoxyphenyl} cyclohexanecarboxylicacid 257 Calc′d 721, found 721.1 7

4-{5-[2-({(4S,5R)-5- [3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3-thiazolidin-3- yl}methyl)-4- (trifluoromethyl)phenyl]-6-methoxypyridin-3- yl}-3-methylbenzoic acid 117 Calc′d 729, found 729.1

1. A compound having formula I, or a pharmaceutically acceptable saltthereof,

Wherein each R is independently H or —C₁-C₃alkyl; R¹ is H or —C₁-C₃alkyl, wherein —C₁-C₃ alkyl is optionally substituted with 1-5 halogens;A and B are each A¹ or A², wherein one of A and B is A¹ and the other ofA and B is A², A¹ has the structure:

wherein D is selected from the group consisting of: (a) phenyl, and (b)HET(1); wherein ring D comprises at least two carbon atoms that arebonded to each other, wherein one of the two carbon atoms that arebonded to each other in ring D is connected to the group A³ and theother of the two carbon atoms that are bonded to each other in ring D isconnected to the remainder of the structure of Formula I, so that A³ andthe remainder of the structure of formula I are ortho to each other onring D; wherein HET(1) is a monocyclic 5-8-membered heterocyclic orheteroaromatic ring having 1-4 heteroatom groups independently selectedfrom N, NH, S, O, —S(O)—, —S(O)₂—, —C(═O)—, and —N(O)—, wherein HET(1)optionally comprises 1-4 double bonds; A³ is (a) phenyl, or (b) HET(1),wherein A³ is optionally substituted with 1-5 substituent groupsindependently selected from R^(a) and optionally one or two groups X;provided that when B is A¹, and D and A³ are both phenyl, then A² isHET(1), or A³ is substituted with one group X, wherein X is phenyl orHET(1); A² is (a) phenyl, (b) HET(1), or (c) —C₃-C₈ cycloalkyloptionally having 1-3 double bonds; wherein A² is optionally substitutedwith 1-5 substituent groups independently selected from R^(a); EachR^(a) is independently selected from the group consisting of —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —OC₂-C₆alkenyl,—OC₂-C₆alkynyl, —C(═O)C₁-C₆alkyl, —C(═O)H, —OH, —NR⁶R⁷, —C(═O)NR⁶R⁷,—NR⁶C(═O)OC₁-C₆ alkyl, —NR⁶C(═O)NR⁶R⁷, —S(O)_(x)C₁-C₆ alkyl,—S(O)_(y)NR⁶R⁷, —NR⁶S(O)_(y)NR⁶R⁷, —NR⁶S(O)_(y)C₁-C₆ alkyl, halogen,—CN, —NO₂, or a 3-7-membered heterocycle having 1-3 heteroatoms whichare independently N, S or O, and optionally one group —C(═O)—, whereinthe heterocycle optionally has 1-3 double bonds and is optionallysubstituted with 1-3 substituent groups which are independently halogen,CH₃, CF₃, —OCH₃, or —OCF₃; wherein for compounds in which R^(a) isselected from the group consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₂-C₆ alkynyl, —OC₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl,—C(═O)C₁-C₆alkyl, —NR⁶C(═O)OC₁-C₆ alkyl, —S(O)_(X)C₁-C₆ alkyl, and—NR⁶S(O)_(y)C₁-C₆ alkyl, R^(a) is optionally substituted with 1-11halogens; X is (a) C₃-C₈cycloalkyl which optionally comprises 1-2 doublebonds and which is optionally substituted with 1-2 groups D1 andoptionally with 1-5 substituent groups which are independently halogen,C₁-C₅ alkyl, —OC₁-C₅ alkyl, —CN, or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅alkyl are optionally substituted with 1-11 halogens and optionally 1-2groups —OH; (b) C₁-C₅ alkyl which is optionally substituted with 1-2groups D1 and optionally with 1-2 —OH and 1-11 halogens; (c) phenylwhich is optionally substituted with 1-2 groups D1 and optionally with1-5 substituent groups which are halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl,—CN, or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionallysubstituted with 1-11 halogens and optionally 1-2 groups —OH; (d) HET(1)which is optionally substituted with 1-2 groups D1 and optionally with1-5 substituent groups which are halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl,—CN, or —OH, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionallysubstituted with 1-11 halogens and optionally with 1-2 groups —OH; or(e) D1; D¹ is —CO₂R⁸, —C(O)NR⁶R⁷, SO₂NR⁶R⁷, or HET(1); R⁶ and R⁷ areeach independently H or —C₁₋₅alkyl; R⁸ is H or —C₁₋₅ alkyl optionallysubstituted with 1-7 halogens; p is an integer from 0-4; x is 0, 1, or2; and y is 1 or
 2. 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein B is A¹ and A is A².
 3. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein B is A²and A is A¹.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Each R is H or CH₃; and p is an integerfrom 0-2.
 5. The compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein R is H.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: D and A³ are eachindependently phenyl, pyridyl, isoxazolyl, thienyl, imidazolyl, furyl,pyrrolyl, pyrazolyl, N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl,1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, or tetrahydrofuryl;and A² is phenyl, thienyl, imidazolyl, furyl, 1,3-thiazolyl,1,3-oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl,N-oxido-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, tetrahydropyranyl, or tetrahydrofuryl.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R is H; R¹ is CH₃; B is A¹, wherein A¹ has the structure offormula II:

wherein Y¹, Y², and Y³ are each N or —CH—, wherein —CH— is optionallysubstituted with R^(a2) in place of H; R^(a1) is (a) a 3-7-memberedheterocycle having 1-2 heteroatoms which are independently N, S or O,and optionally one group —C(═O)— wherein the heterocycle optionally has1-3 double bonds and is optionally substituted with 1-3 substituentgroups which are independently halogen, CH₃, CF₃, —OCH₃, or —OCF₃; (b)—NR⁶R⁷; (c) —N(C₁-C₃ alkyl)(SO₂C₁-C₃alkyl); (d) C₁-C₃ alkyl optionallysubstituted with 1-7 halogens; (e) —OC₁-C₃ alkyl optionally substitutedwith 1-7 halogens; and (f) —SC₁-C₃ alkyl optionally substituted with 1-7halogens; Each R^(a2) is optionally halogen, CH₃, CF₃, —OCH₃, or —OCF₃;A is A², wherein A² is phenyl or pyridyl optionally substituted with 1-3groups which are independently halogen, CH₃, CF₃, —OCH₃, —OCF₃, or —CN;A³ is phenyl or pyridyl, which is optionally substituted with one groupX and with 1-4 substituent groups which are independently halogen, C₁-C₃alkyl optionally substituted with 1-7 halogens, or —OC₁-C₃ alkyloptionally substituted with 1-7 halogens; X is (a) C₃-C₇cycloalkyloptionally substituted with one group D1, and cycloalkyl is optionallysubstituted with 1-3 substituent groups which are independently halogen,—OH, C₁-C₃ alkyl, or —OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and —OC₁-C₃alkyl are optionally substituted with 1-5 halogens and optionally with1-2 groups —OH; (b) C₁-C₃ alkyl-D1 in which alkyl is optionallysubstituted with 1-7 halogens and optionally with 1-2 —OH; (c) phenyloptionally substituted with one group D1, wherein phenyl is optionallysubstituted with 1-3 substituent groups which are halogen, —OH, C₁-C₃alkyl, or —OC₁-C₃ alkyl in which C₁-C₃ alkyl and —OC₁-C₃ alkyl areoptionally substituted with 1-7 halogens and optionally with 1-2 OH; (d)pyridyl which is optionally substituted with one group D1, whereinpyridyl is optionally substituted with 1-3 substituent groups which arehalogen, —OH, C₁-C₃ alkyl, or —OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and—OC₁-C₃ alkyl are optionally substituted with 1-7 halogens andoptionally with 1-2 groups —OH; or (e) D1; D¹ is —CO₂R⁸; R⁶ and R⁷ areeach independently H or —C₁₋₅alkyl; R⁸ is H or —C₁₋₅alkyl optionallysubstituted with 1-7 halogens; and d is 0, 1 or
 2. 8. The compound ofclaim 1 having formula I or a pharmaceutically acceptable salt thereof,wherein R is H; R¹ is CH₃; B is A¹, wherein A¹ has the structure offormula II:

Y¹, Y², and Y³ are each —CH— or —N—; A is A² wherein A² is phenyl orpyridyl optionally substituted with 1-3 groups independently selectedfrom F, —CN, CH₃, CF₃, —OCH₃, —OCF₃; R^(a1) is —CF₃; A³ is

wherein Z is —CH— or —N—; X is 4-cyclohexyl-D¹, 4-phenyl-D¹ optionallysubstituted with 1-2 —CH₃ groups, —CH₂CH₂D¹, cyclopentyl optionallysubstituted with 1-2 —OH groups, HET(1), or isopropyl, wherein D¹ is—CO₂R⁸; R⁸ is H or —CH₃; R^(b) is —OCH₃ or halogen; d is 0; and e is aninteger from 0-3.
 9. The compound of claim 8, or a pharmaceuticallyacceptable salt thereof, wherein: Y¹ and Y³ are —CH—; Y² is —CH— or —N—;A² is phenyl which is substituted with 2 groups CF₃;
 10. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, having thestructure below:


11. A pharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 12. A method of treating atherosclerosis in apatient in need of treatment comprising the administration of atherapeutically effective amount of the compound of claim 1 to saidpatient, or a pharmaceutically acceptable salt thereof.
 13. A method ofraising HDL-C in a patient in need of treatment comprising theadministration of a therapeutically effective amount of the compound ofclaim 1 to said patient, or a pharmaceutically acceptable salt thereof.14. A method of lowering LDL-C in a patient in need of treatmentcomprising the administration of a therapeutically effective amount ofthe compound of claim 1 to said patient, or a pharmaceuticallyacceptable salt thereof.
 15. A method of treating dyslipidemia in apatient in need of treatment comprising the administration of atherapeutically effective amount of the compound of claim 1 to saidpatient, or a pharmaceutically acceptable salt thereof. 16-17.(canceled)
 18. A pharmaceutical composition comprising the compound ofclaim 1 or a pharmaceutically acceptable salt thereof, apharmaceutically acceptable carrier, and one or more active ingredientsselected from the group consisting of: (i) HMG-CoA reductase inhibitors;(ii) bile acid sequestrants; (iii) niacin and related compounds; (iv)PPARα agonists; (v) cholesterol absorption inhibitors; (vi) acylCoA:cholesterol acyltransferase (ACAT) inhibitors; (vii) phenolicanti-oxidants; (viii) microsomal triglyceride transfer protein(MTP)/ApoB secretion inhibitors; (ix) anti-oxidant vitamins; (x)thyromimetics; (xi) LDL (low density lipoprotein) receptor inducers;(xii) platelet aggregation inhibitors; (xiii) vitamin B12 (also known ascyanocobalamin); (xiv) folic acid or a pharmaceutically acceptable saltor ester thereof; (xv) FXR and LXR ligands; (xvi) agents that enhanceABCA1 gene expression; (xvii) ileal bile acid transporters; and (xviii)niacin receptor agonists.